The present invention relates to an immunological tolerance-inducing agent containing a nucleic acid-polysaccharide complex of an siRNA for a costimulatory factor and schizophyllan. Also, the present invention relates to a method for inducing immune tolerance by inhibiting gene expression of a costimulatory factor using the nucleic acid-polysaccharide complex to control the function of Dectin-1 expressing cell such as a dendritic cell, and to a medicine for use in the method. Especially, the present invention relates to a medicine containing a nucleic acid-polysaccharide complex of an siRNA for a costimulatory factor and schizophyllan, which inhibits rejection occurring in organ transplantation and induces immune tolerance.
RNA interference (RNAi) discovered in 1998 has markedly superior efficacy and persistence to conventional antisense methods and is a breakthrough gene expression inhibitory method, and therefore there has been a hope for its pharmaceutical applications. However, a double strand RNA (i.e., siRNA) that shows an RNAi activity is often decomposed during the process from administration to uptake into a target cell or decomposed in a cell, and it has been difficult to form a RISC complex, i.e., its active substance, in a cell. Accordingly, even though it is a superior gene expression inhibitory method, a sufficient effect is not obtainable, and therefore a pharmaceutical product that uses an siRNA is not yet available.
Unmodified siRNAs are decomposed by nuclease that is present in, for example, blood, and few unmodified siRNAs demonstrate an RNAi effect in a target cell. Accordingly, various chemical modifications to give nuclease resistance have been performed on siRNAs. Nevertheless, a high dosage is necessary for effective introduction into a cell. Also, it is known that because administration of a double strand nucleotide into a living body in a high dosage enhances a natural immunoreaction, an unintended effect, i.e., immunostimulatory reaction, appears. Accordingly, a delivery technique to specifically introduce an siRNA into a target cell is necessary. For siRNA delivery techniques, techniques to embed an siRNA, such as liposomes and macromolecular nanomicelles, have been developed. However, in terms of target tropism, these delivery techniques are still within the meaning of passive targeting, and in order to overcome this shortcoming, a procedure for imparting, for example, a molecule that binds to the target cell to an siRNA drug is needed.
With such conventional art as background, a demand exists for positive targeting and a delivery technique for an siRNA that shows an RNAi activity significantly within the target cell. Accordingly, as a delivery method of an siRNA to a dendritic cell, a complex of schizophyllan and a polydeoxyadenine-added siRNA has been proposed (see WO 2009/078470).
Meanwhile, transplantation therapy, in which a donor cell, tissue or organ is transplanted to a patient with organ failure, hematological malignancy or the like, has been established and become a crucial therapy in clinical practice. In transplantation therapy, however, technical improvement for inhibiting donor-specific immunoreaction in a recipient is still demanded. Previously, to prolong the transplanted organ survival in organ transplantation, attempts to block CD40-CD40L pathway or CD28-B7 pathway by various antibodies have been made, but no technique that is capable of effective induction of donor-specific tolerance and put into practical use has been found (See Exp Neurol. 2004 March; 186(1): 59-69; Transplantation 2003; 75(5): 637-643).